Batch chromatography is well known and routinely and preparatively applied in industrial productions. The technique is however rather costly in particular for large scale separation and purification due to high solvent consumption and expensive column material, and it requires an optimal use of the chromatographic equipment to be profitable.
For large scale separations in actual productions continuous processes are much more economic than batch processes. The advantages of a continuous process is for example high yield, less solvent consumption (recovery), less costly fractionation and analyses, better flexibility for the quantities to be purified etc.
One way to realize a continuous chromatographic process is the so called Simulated Moving Bed Process (SMB, for a review see e.g. Markus Juza, Marco Mazzotti and Massimo Morbidelli, Simulated moving-bed chromatography and its application to chirotechnology, Trends in biotechnology, Elsevier B. V., TIBTECH, March 2000, Vol. 18, p 108-118). This process can separate a mixture into two fractions by adjusting two inlet streams (feed, eluent) and two outlet streams (raffinate, extract). The SMB process is countercurrent so that a well-defined separation of the two fractions is possible at high yields. Typical examples for SMB technique in the industry are chiral separations, where two enantiomers are separated from a racemic mixture. If the selectivities are very small, usually a batch process results in rather small yields while however SMB allows to have high purity and high yields.
Various modifications of the SMB process have been proposed in order to optimise and tailor it to specific problems. So it has for example been proposed to vary the instants of individual connection and disconnection of the inlet streams and the outlet streams, i.e. inlet streams and outlet streams are not switched concomitantly as in classical SMB, but according to a specific and staged scheme (so-called Varicol-technique, see for example WO-A-2004/039468).
Another variation has been proposed by Morbidelli et al (see for example “PowerFeed operation of simulated moving bed units: changing flow-rates during the switching interval” by Ziyang Zhang, Marco Mazzotti, Massimo Morbidelli, Journal of Chromatography A, 1006 (2003) 87-99, Elsevier B. V.), in that in order to compensate the time-variation in the concentration of the output of the extract and raffinate due to the discrete switching after each cycle time the flow rate of the eluent is varied in a compensating manner coordinated to the switching interval, allowing to have even higher purity (so-called Powerfeed-technique).
A third and quasi-analogous variation has been proposed in that not the flow rate of the eluent but the concentration of the feed is varied in a compensating manner to achieve the same goal (so-called Modicon technique, see for example WO 2004/014511).
As already mentioned, in particular large scale chromatography is a laborious and expensive technique. It is only useful for the large scale separation of valuable molecules. The most valuable molecules on the market are biomolecules like for example peptides, proteins and antibodies. These molecules are usually purified via solvent gradient batch chromatography. In contrast to the term “separation”, which in the context of this applications shall stand for the separation of a mixture into two fractions, “purification” means that the desired product is an intermediate between light and heavy adsorbing impurities, and that three fractions are generated. One SMB cycle can only split the feed stream into two fractions (separation), but for purifications, three fractions are required with the desired component in the intermediate fraction. Two staged or sequential SMB would be required to purify a multicomponent mixture with an intermediate desired biomolecule and heavy and light impurities however with the problem that if e.g. in a first stage SMB a first raffinate and a first extract is generated and in a second stage SMB the first extract is separated in a second raffinate (desired product) and a second extract, all undesired constituents which should have been separated in the first stage (and should have ended in the first raffinate) will certainly end up in the second raffinate which in particular for low concentrations of the desired fraction makes such processes useless.
Apart from the above, also other modifier variations were applied to the SMB scheme, such as for a few years SMB processes are operated also in so-called “solvent gradient mode” (see e.g. U.S. Pat. No. 4,031,155). The meaning of this “solvent gradient” is that the SMB contains sections, which operate on different modifier levels. This type of gradient is a “step gradient”. For the purification of biomolecules however a smooth linear gradient would be desired, as routinely applied in (linear) solvent gradient batch purifications.